Beta-thalassemia, one of the most common inherited hemoglobinopathies worldwide, is due to autosomal mutations in the gene encoding β-globin which induce an absence or low-level synthesis of this protein in erythropoietic cells (Weatherall D J, 2001, Nature Reviews Genetics; 2(4):245-255). About 80 to 90 million people (˜1.5% of the global population) are carriers of beta-thalassemia with approximately 60,000 symptomatic individuals born annually (Modell et al., 2007, Scand J Clin Lab Invest; 67:39-69). The annual incidence of symptomatic individuals is estimated at 1 in 100,000 worldwide and 1 in 10,000 in the European Union (EU) (Galanello R and Origa R, 2010, Orphanet J Rare Dis; 5:11). Incidence is highest in the Mediterranean region, the Middle East, and South East Asia (particularly India, Thailand and Indonesia; this region accounts for approximately 50% of affected births) and incidence is increasing worldwide (e.g., Europe, the Americas and Australia) as a result of migration (Colah R, Gorakshakar et al., 2010; Expert Rev Hematol; 3(1):103-17; Modell et al., 2008, Bull World Health Organ; 86(6):480-7).
Beta-thalassemias are characterized by a reduction of β-globin chains and a subsequent imbalance in globin chains (α:non-α ratio) of the hemoglobin (Hb) molecule, which results in impaired erythropoiesis and other complications. Nearly 200 different mutations have been described in patients with beta-thalassemia that affect the beta-globin gene, for which patients may be either homozygous or compound heterozygous. Phenotypic effects, therefore, range widely in patients from slight impairment to complete inhibition of beta-globin chain synthesis (Thein S L, 2013, Cold Spring Harb Perspect Med; 3(5):a011700). In addition to deficient β-globin chains, patients may also present with β-thalassemia combined with structural variants such as HbE, leading to HbE/beta-thalassemia.
Given the current lack of safe and effective drug therapies to treat beta-thalassemia, for example, transfusion-dependent and non-transfusion-dependent beta-thalassemia, there is significant unmet medical need for the development of new therapies that specifically address the underlying pathophysiology of beta-thalassemia syndromes including anemia and complications of ineffective erythropoiesis, for methods of diagnosing beta-thalassemia, and for methods of monitoring treating of beta-thalassemia.
Two related type II receptors, ActRIIA and ActRIIB, have been identified as the type II receptors for activins (Mathews and Vale, 1991, Cell 65:973-982; Attisano et al., 1992, Cell 68: 97-108). Besides activins, ActRIIA and ActRIIB can biochemically interact with several other TGF-beta family proteins, including BMP7, Nodal, GDF8, and GDF11 (Yamashita et al., 1995, J. Cell Biol. 130:217-226; Lee and McPherron, 2001, Proc. Natl. Acad. Sci. 98:9306-9311; Yeo and Whitman, 2001, Mol. Cell 7: 949-957; Oh et al., 2002, Genes Dev. 16:2749-54). ALK4 is the primary type I receptor for activins, particularly for activin A, and ALK-7 may serve as a receptor for activins as well, particularly for activin B.
ActRII signaling inhibitors have been demonstrated to increase red blood cell levels and treat ineffective erythropoiesis (see, e.g., U.S. Pat. No. 7,988,973 and U.S. patent application Ser. No. 13/654,191, respectively, which are incorporated herein by reference in their entireties). Moreover, an activin ligand trap, consisting of a humanized fusion-protein consisting of the extracellular domain of activin-receptor type IIA (ActRIIA) and the human IgG1 Fc (ActRIIA-hFc), is currently being evaluated in phase II clinical trials for treatment of subjects with beta-thalassemia. An activin ligand trap, consisting of a humanized fusion-protein consisting of the extracellular domain of activin-receptor type IIB (ActRIIB) and the human IgG1 Fc (ActRIIB-hFc), is currently being evaluated in phase II clinical trials for treatment of subjects with beta-thalassemia.